JP7181821B2 - automatic analyzer - Google Patents

Description

The present invention relates to an automatic analyzer equipped with a pipetting unit for sucking and discharging liquid, and more particularly, an automatic analyzer equipped with a function of predicting the state of a liquid during pipetting, such as air entrapment or clogging in a pipe. Regarding.

Automatic analyzers such as biochemical analyzers and immunoanalyzers have a sample dispensing unit that aspirates a specified amount of a sample such as a biological sample and discharges it into a reaction container, and a sample dispensing unit that aspirates a specified amount of test reagent and discharges it into a reaction container. It is composed of a reagent dispensing unit and a detection unit that detects a mixture of reacted sample and reagent.
Here, the specimen dispensing unit and the reagent dispensing unit are composed of a cylindrical or tapered probe to be inserted into the liquid, a syringe to drive suction and discharge of the liquid, and a channel connecting the probe and the syringe. A specified amount of liquid is dispensed by inserting the probe into the liquid, aspirating a specified amount of liquid, moving the probe to a different container, and discharging. In sample dispensing, a disposable tip may be attached to the tip of the probe in order to prevent sample components from being carried over to the next examination.

Dispensing abnormalities can occur during liquid dispensing, such as suction of air bubbles generated by sample container handling, clogging of channels due to fibrin such as fibrin in high-viscosity liquids and samples. Accurate analysis results can be obtained by accurately estimating the dispensing state and detecting abnormalities.

As a method for detecting an abnormality in dispensing, for example, in Patent Document 1, the pressure integral value in a specific interval with respect to the pressure fluctuation during sample ejection and the average pressure difference between the steady ejection and the end of ejection are used as indices. is compared with a preset threshold value to detect a specimen dispensing abnormality.
Further, in Patent Document 2, a configuration is adopted in which the internal pressure of the flow path during sample aspiration is recorded, and the sample aspiration abnormality is detected by comparing the recorded aspiration pressure curve with a parameterized formula.

Japanese Patent No. 3633631 Japanese Patent Application Laid-Open No. 2000-121649

The structure disclosed in Japanese Patent Laid-Open No. 2002-200011 uses the integrated pressure value in a specific section and the average pressure difference between the time of steady discharge and the end of discharge as indices for pressure fluctuations during sample discharge, and uses these as preset threshold values. The dispensing state is detected by comparison. However, if the amount to be dispensed is small and there is no significant difference in the pressure waveform, or if there is an overlap between the pressure fluctuation used to detect the dispensing status and the pressure pulsation due to the probe operation before and after dispensing, the dispensing status Prediction accuracy may decrease. As a result, an erroneous judgment that normal dispensing is judged to be abnormal or an oversight of judging an abnormality as normal necessitates an additional test, which may cause loss of specimens and reagents.
In addition, the structure shown in Patent Document 2, which records the pressure inside the flow path during sample aspiration and compares the recorded aspiration pressure curve with a parameterized formula, is effective when smooth pressure fluctuations occur during aspiration. is. On the other hand, if the pipetting syringe operation or probe operation before and after dispensing causes pulsation in the pressure inside the flow path, the accuracy of predicting the dispensing state may decrease, and loss of specimens and reagents may occur. There was a problem.

Accordingly, the present invention provides an automatic analyzer capable of estimating a dispensing state with high accuracy even when pressure pulsation occurs due to a dispensing syringe operation or a probe operation before and after dispensing.

In order to solve the above problems, an automatic analyzer according to the present invention has a container filled with a fluid and a pressure source, a probe for dispensing the fluid in the container, a driving unit for moving the probe, a flow path connecting the probe and the pressure source; a pressure sensor for measuring pressure fluctuations in the flow path; a storage unit for storing time-series measurement data from the pressure sensor; and a position determination unit that determines the position of the flow path or the probe, and the pressure calculated based on the time-series measurement data and the position information of the flow path or the probe by the position determination unit. It is characterized by estimating the state of the flow generated in the flow path based on the fluid pressure based on the gravitational acceleration at the position of the sensor .
Further, an automatic analyzer according to the present invention includes a container filled with a fluid and a pressure source, a probe for dispensing the fluid in the container, a drive unit for moving the probe, the probe and the pressure source. a flow path that connects a source, a pressure sensor that measures pressure fluctuations in the flow path, a storage unit that stores time-series measurement data of the pressure sensor, a sensor that detects the liquid level position in the container, a position determination unit that determines the position of the flow path or the probe, and the flow generated in the flow path based on the time-series measurement data and the position information of the flow path or the probe obtained by the position determination unit. is estimated, the pressure pulsation is calculated according to the flow channel position and the operation history of the flow channel, and the calculated pressure pulsation is subtracted from the time-series measurement data.

According to the present invention, it is possible to provide an automatic analyzer capable of detecting the dispensing state with high accuracy even when pressure pulsation occurs due to the dispensing syringe operation or the probe operation before and after dispensing.
Problems, configurations, and effects other than those described above will be clarified by the following description of the embodiments.

1 is a schematic configuration diagram of an automatic analyzer of Example 1 according to an embodiment of the present invention; FIG. FIG. 2 is a schematic configuration diagram of a specimen dispensing mechanism of the automatic analyzer shown in FIG. 1; FIG. 10 is a diagram showing the state of fluid movement within the chip during air suction for sucking and discharging air bubbles. FIG. 10 is a diagram representing pressure fluctuations in the aspiration or ejection process; It is a figure which shows a probe, a pressure sensor, and the flow path which connects them. FIG. 10 is an operation flow of the specimen dispensing mechanism, showing a dry aspiration determination procedure; It is a figure which shows the preparation procedure of a relative pressure waveform. It is a figure which shows the preparation procedure of pressure waveform reference|standard. FIG. 3 is a modification of the schematic configuration diagram of the specimen dispensing mechanism of the automatic analyzer shown in FIG. 2; FIG. 10 is a diagram showing a procedure for determining a certain constant α in the modified example shown in FIG. 9; FIG. 10 is a diagram showing a dry suction determination procedure of Example 2 according to another example of the present invention; FIG. 4 is a diagram showing pressure data before and after pressure pulsation processing;

Hereinafter, embodiments of the present invention will be described with reference to the drawings.

First, in this embodiment, a case of detecting suction of air bubbles (hereinafter referred to as dry suction), which is one of dispensing states, will be described.
FIG. 1 is a schematic configuration diagram of an automatic analyzer 101 of Example 1 according to one embodiment of the present invention.
As shown in FIG. 1, an automatic analyzer 101 includes a rack transport line 103 that transports a sample rack 102, a reagent cooling unit 104, an incubator disk (reaction disk) 105, a sample dispensing mechanism (sample dispensing mechanism) 106, a reagent A dispensing mechanism 107 , a consumable transport unit 108 , and a detector unit 109 are provided.

The sample rack 102 accommodates a plurality of sample containers (sample containers) 110 containing biological samples (specimens) such as blood and urine. be transported.

In the reagent cooling unit 104, a plurality of reagent containers 111 containing various reagents used for analysis of samples are accommodated and kept cool. At least part of the upper surface of the reagent cooling unit 104 is covered with a reagent disk cover 112 .

The incubator disk 105 has a reaction container placement section 114 in which a plurality of reaction containers 113 for reacting specimens and reagents are arranged, and a temperature control mechanism (not shown) for adjusting the temperature of the reaction containers 113 to a desired temperature. have.

The sample pipetting mechanism 106 has a rotation drive mechanism and a vertical drive mechanism (not shown), and by these drive mechanisms, the sample can be pipetted from the sample container 110 to the reaction container 113 housed in the incubator disk 105. It is possible. Similarly, the reagent dispensing mechanism 107 has a rotation driving mechanism and a vertical driving mechanism (not shown), and these driving mechanisms dispense the reagent from the reagent container 111 to the reaction container 113 housed in the incubator disk 105. . The detector unit 109 includes a photomultiplier tube, a light source lamp, a spectroscope, and a photodiode (not shown), has a function of adjusting their temperatures, and analyzes the reaction solution.

FIG. 2 is a schematic configuration diagram of a specimen dispensing mechanism of the automatic analyzer shown in FIG. As shown in FIG. 2, a probe 202 with a freely detachable tip 201 is connected to a syringe 204 via a channel 203, and the interior thereof is filled with liquid. The syringe 204 is composed of a cylinder 204a and a plunger 204b, and a syringe driving section 205 is connected to the plunger 204b. By driving the plunger 204b up and down with respect to the cylinder 204a by the syringe drive unit 205, the sample is aspirated and discharged. A motor (not shown) is connected to the probe 202 as a probe drive unit 206, which can move the probe 202 horizontally and vertically to a predetermined position. Note that the syringe drive unit 205 and probe drive unit 206 are controlled by the control unit 207 .

When a specimen (sample) 209 in a container 208 is aspirated, prior to the aspiration operation, air (segmental air) is introduced into the probe 202 to prevent the liquid filled in the probe 202 from mixing with the specimen 209. Aspirate and attach the tip 201 to the tip of the probe 202 . After that, the probe drive unit 206 lowers the probe 202 until the tip of the tip 201 reaches the liquid of the specimen 209, and further performs a suction operation. When the specimen aspirating operation is completed, the probe 202 moves to the specimen ejection position, and the syringe 204 performs the ejection operation.

After the discharge, the water supply pump 210 discharges the cleaning water 212 in the water supply tank 211 at high pressure, so that the probe 202 can be washed. A solenoid valve 213 opens and closes the flow path to the water supply tank 211 . Note that the solenoid valve 213 is controlled by the controller 207 .

A pressure sensor 214 for measuring the pressure inside the channel 203 is connected to the channel system including the probe 202 , the channel 203 and the syringe 204 via a branch block 215 . Here, the pressure sensor 214 is preferably installed on the probe 202 side as much as possible in order to measure the pressure fluctuations at the openings of the probe 202 and the tip 201 with high sensitivity. The output value of pressure sensor 214 is amplified by signal amplifier 216 and converted to a digital signal by A/D converter 217 . The digitally converted signal is sent to the determination section 218 .

The determination unit 218 includes a sampling unit 219 that samples the signal from the A/D converter 217, a storage unit 220 that stores the data of the sampling unit, and a calculation that calculates an average value from the information stored in the storage unit 220. and a part 221 .

The liquid level sensor 222 determines whether the tip 201 at the tip of the probe 202 is immersed in the specimen 209 during dispensing. Information on the relative immersion depth of the probe 202 calculated from the immersion time with respect to the specimen 209 is sent to the storage unit 220 .

A channel position determination unit 223 determines the positions of the probe 202 and the channel 203 at the time of dispensing. The specific configuration of the channel position determination unit 223 includes a mechanism for determining the height of the probe 202 based on the driving history of the motor of the probe driving unit 206, a mechanism for detecting the positions of the probe 202 and the channel 203 with a sensor, etc. etc. Position information of the probe 202 and the channel 203 at the time of dispensing determined by the channel position determination unit 223 is sent to the storage unit 220 .
The determination results performed by the determination unit 218 and the countermeasures for the determination results are displayed to the user using the display unit 224 . Also, operation change information based on the determination result is transmitted to the control unit 207 .

The determination unit 218 may be configured as hardware in the apparatus as a dedicated circuit board, or may be input/output using hardware near or at a remote location of the apparatus and using an information communication network.

FIG. 3 shows fluid movement in the tip during dry aspiration, which is one of the dispensing states. The upper diagram in FIG. 3 shows fluid movement during suction, and the lower diagram in FIG. 3 shows fluid movement during ejection. Air bubbles 301 are erroneously sucked into the tip 201 when the sample 209 is sucked, resulting in dry suction. One possible cause of dry suction is erroneous detection of the liquid surface due to air bubbles that are unintentionally generated during sample container handling.

The pressure loss in the channel due to the viscosity of the fluid is different when comparing the movement of bubbles in the chip and the movement of the specimen. The following Hagen-Poiseuille formula (1) is an example of a physical formula that expresses pressure loss due to friction in a pipeline.
P _loss =128 μLQ/(πd ⁴ ) (1)
Here, P _loss is the pressure loss, μ is the viscosity of the fluid, L is the length of the pipeline, π is the circumference constant, d is the diameter of the pipeline, and Q is the flow rate in the pipeline. In this embodiment, the dry suction state is detected using the pressure data of the suction process or the discharge process in which flow occurs in the pipeline.

FIG. 4 is a diagram representing pressure fluctuations during the aspiration or ejection process. As shown in FIG. 4, the probe starts to descend at a time 401 when the horizontal rotational movement of the probe to the sample container 110 stops, and between the time 402 when the probe descent stops and the dispensing syringe operation start time 403, the inertial force of the descent stops. Attenuated oscillation, pressure oscillation due to flow in the pipeline occurs between dispensing syringe operation start time 403 and dispensing syringe operation end time 404 . Of these, the influence of air bubbles in the chip 201 appears in pressure vibrations due to flow in the channel between the dispensing syringe operation start time 403 and the dispensing syringe operation end time 404 . Therefore, it is effective to use this interval in detecting dry sucking.

In the present embodiment, relative pressure values between the dispensing syringe operation start time 403 and the dispensing syringe operation end time 404 are based on the pressure between the probe lowering stop time 402 and the dispensing syringe operation start time 403 as the reference pressure value. to determine the air sucking. By using the pressure between the probe descent stop time 402 and the dispensing syringe operation start time 403 as a reference, empty aspiration detection can be performed without being affected by the difference in height during dispensing. Moreover, depending on the length of the dispensing operation time, the effect of air bubbles may appear even after the dispensing syringe operation end time 404 . In this case, pressure data after the dispensing syringe operation end time 404 may be used for determination.

Here, when the probe descent stop time 402 and the dispensing syringe operation start time 403 are close to each other by one second or less, the reference pressure value may be affected by damped oscillation due to inertial force. In order to use a stable reference pressure value without being affected by this damped oscillation, the immersion depth information from the liquid level sensor 222 and the probe height information from the flow path position determination unit 223 are used.

FIG. 5 shows probes, pressure sensors, and channels connecting them in the sample pipetting mechanism of FIG.
In FIG. 5, the fluid pressure Phead based on the gravitational acceleration at the pressure sensor position is expressed by the following equation (2).
Head=ρg(H+h) (2)
Here, ρ is the density of the fluid in the probe, channel, and sample cup, g is the gravitational acceleration, H is the probe height, and h is the immersion depth. If the tip, probe, channel, and sample cup contain fluids with different densities, it is preferable to calculate the fluid pressure based on the gravitational acceleration for each fluid.

In this embodiment, the reference pressure value between the probe downward stop time 402 and the dispensing syringe operation start time 403 was calculated from the immersion depth information h obtained by the liquid level sensor 222 and the probe height H obtained by the flow path position determination unit 223. The fluid pressure Phead based on the gravitational acceleration is used as the reference pressure value. By using this Phead as the reference pressure value, damping vibration due to inertial force is not affected.

FIG. 6 shows an operation flow of the specimen dispensing mechanism, which is a flow chart for dry aspiration determination in this embodiment.
The following dry aspiration judgment is performed when dispensing the sample input by the user and the reagent used for analysis. First, in step S601, the probe drive unit 206 and the channel position determination unit 223 stop descending the probe before dispensing and acquire probe height information. After that, in step S602, the syringe drive unit 205 executes dispensing syringe operation and time-series pressure data collection. In step S603, the calculation unit 221 calculates the reference pressure value by the above equation (2), and the relative pressure between the dispensing syringe operation start time 403 and the dispensing syringe operation end time 404 with respect to the reference pressure value P _head . A waveform is created (step S604).
Here, in creating the relative pressure waveform in step S604, it is necessary to match the positions of the relative pressure waveforms in the time direction. In this embodiment, the reference pressure value calculated by the reference pressure value calculation (step S603) is used to perform position alignment in the time direction.

FIG. 7 shows the procedure for creating the relative pressure waveform.
As shown in the upper diagram of FIG. 7, first, in step S701, the calculation unit 221 calculates the threshold pressure. The threshold pressure is used as a trigger for determining the time reference point when performing time direction alignment of the relative pressure waveforms. Here, the reference pressure value 701a calculated in the above step S603 (reference pressure value calculation) is offset by a constant value to be a threshold pressure 701b (lower diagram in FIG. 7). This offset may be constant for all pipetted amounts or may vary for each pipetted amount. By setting the threshold pressure 701b based on the reference pressure value 701a, it is possible to create a relative pressure waveform that is not affected by the probe height and immersion depth during dispensing.

Using the calculated threshold pressure 701b, the calculator 221 calculates the reference time in step S702. A reference time 702a (lower diagram in FIG. 7) is a time corresponding to the threshold pressure 701b and is used to align the pressure pulsation due to the syringe operation in the time direction. In determining the reference time 702a, it is preferable to use the dispensing syringe operation start time 403 to narrow down the search range for the time corresponding to the threshold pressure 701b. Since the pressure pulsation due to the syringe operation occurs after the dispensing syringe operation start time 403, it is desirable to search for a certain period of time after the dispensing syringe operation start time 403. FIG. Also, it is desirable to set the threshold pressure 701b at a point where the gradient of the pressure pulsation is large. By setting the point at which the gradient of the pressure pulsation is large, it is possible to improve the accuracy of determining the reference time 702a in the time direction. In searching for the reference time 702a, it is desirable to determine the reference time 702a using known interpolation techniques such as linear interpolation and spline interpolation for discrete time-series data.

In step S703, the calculation unit 221 offsets the pressure waveform using the calculated threshold pressure 701b and the reference time 702a. In the pressure waveform offset (step S703), the obtained time-series pressure data is translated such that the point corresponding to the threshold pressure 701b and the reference time 702a becomes the origin 703a. By offsetting the pressure waveform (step S703), it is possible to cancel the pressure waveform difference due to the difference in water head due to the probe height and immersion depth and the difference in suction time, and to extract only the pressure fluctuation due to the dispensing syringe operation with high accuracy. .

Returning to FIG. 6, in step S605, the calculator 221 compares the relative pressure waveform with the pressure waveform reference. Here, the pressure waveform reference is a pressure waveform obtained in advance, and dry suction is determined by comparing the relative pressure waveform and the pressure waveform reference. As the pressure waveform reference, a pre-obtained pressure waveform during normal dispensing or a pressure waveform during dry suction can be used. This is, for example, to suppress the machine difference for each syringe.

Comparison of the relative pressure waveform and the pressure waveform reference during dispensing (step S605) compares known statistical distances such as the average value of the pressure in a certain interval, the integrated value of the pressure, the Euclidean distance between the two waveforms, and the Mahalanobis distance. can be used for Since both the relative pressure waveform and the pressure waveform reference include the pressure pulsation during the operation of the dispensing syringe, we can compare the relative pressure waveform and the pressure waveform reference to determine the dispensing state that is not caused by the pressure pulsation due to the operation of the dispensing syringe. detection is possible.

In step S606, the calculation unit 221 determines the dispensing state from the result of comparison between the relative pressure waveform and the pressure waveform reference. Judgment of the dispensing state is made by comparing the relative pressure waveform at the time of dispensing with the pressure waveform reference (step S605), and determining the magnitude of the average value of the pressure in a certain interval, the integrated value of the pressure, and a certain threshold value. and the magnitude relation of values such as Euclidean distance and Mahalanobis distance with respect to a plurality of pressure waveform references. If it is determined to be normal (step S607), subsequent analysis operations are performed on the sample, and if it is determined to be dry suction (step S608), analysis of the sample is canceled or an alert is issued. It is recommended to display a message prompting re-analysis. Further, an operation for compensating for dry suction, such as re-executing the dispensing process, may be performed. The reliability of the analysis results can be secured by canceling the analysis or issuing an alert.

FIG. 8 shows the procedure for creating the pressure waveform reference, and shows the detailed procedure for creating the pressure waveform reference in step S605 of FIG. Note that the following steps are executed by the calculation unit 221 .

When the service engineer or the user sets the calibration mode (step S801), the creation of the pressure waveform reference is started. A service engineer or a user installs a predetermined calibration sample (step S802) in the apparatus. Here, it is desirable that the specimens used as calibration specimens include both specimens that serve as a reference for normal dispensing and specimens that serve as a reference for dry aspiration. The standard for normal dispensing should be set to the one with the lowest viscosity among the samples that can be analyzed by the device. If the sample with the lowest viscosity among the samples that can be analyzed by the device is about the same as pure water, the standard for normal dispensing is the same or less than the viscosity of pure water. If a specimen with a viscosity of 1.5 mPa·s or less is set as a standard for normal dispensing under the environment of , highly accurate determination can be made for all specimens. In addition, it is desirable to use a specimen containing gas as a reference for dry aspiration. To reduce variability, it is preferable to set up a completely empty sample cup. Two or more criteria for normal dispensing or criteria for dry aspiration may be set as calibration specimens. At this time, it is desirable that the amount of the calibration sample to be dispensed into the sample cup is set near the median value between the upper limit and the lower limit of the liquid surface height that can be analyzed by the device. If necessary, a pressure waveform reference may be created by setting a dispensing amount corresponding to a plurality of liquid level heights.

A calibration pipetting cycle is started (step S803) for the installed calibration sample, and the pipetting cycle is executed a specified number of times (step S804). Here, it is desirable that the dispensing cycle should be the same as the operation during analysis of the actual sample. In addition, while the dispensing cycle is being executed a specified number of times (step S804), probe height information is acquired when the probe stops descending before dispensing, and time-series pressure data is collected when the dispensing syringe is operating, and the collected data is stored. Record in section 220 . Dispense may be performed for multiple dispense volumes and calibration dispense volumes may be set to cover all possible syringe motion speeds. Since the pressure pulsation during syringe operation is highly dependent on the syringe operation speed, multiple pressure waveform standards were created to cover all possible syringe operation speeds, thereby avoiding the effects of pressure pulsation during syringe operation. It is possible to realize a dry suction judgment that does not occur. In addition, it is desirable to dispense both the standard specimen for normal dispensing and the standard specimen for dry aspiration with respect to the same dispensing amount, and further dispense both a plurality of times. When the same sample is dispensed multiple times with the same dispensed volume, the time-series pressure data at the time of multiple dispensations are compared, and by confirming that the difference is small, the reliability of the pressure waveform reference is improved. be able to. Here, in order to confirm that the difference is small, the average value of the pressure in a certain interval, the integrated value of the pressure, the Euclidean distance between the two waveforms, the Mahalanobis distance, etc. can be used.

After the dispensing cycle is executed a specified number of times (step S804), the probe height information obtained when the probe stops descending before dispensing recorded in the storage unit 220 and the time-series pressure data when the dispensing syringe operates are used to obtain the reference Pressure value calculation (step S805) and creation of relative pressure waveform (step S806) are performed. It is desirable that the reference pressure value calculation (step S805) is the same as the reference pressure value calculation (step S603), and the relative pressure waveform creation (step S806) is the same as the relative pressure waveform creation (step S604). By performing the same processing, when comparing the pressure waveform reference and the relative pressure waveform at the time of determination, it is possible to detect the dispensing state without depending on the probe height, immersion depth, or pressure pulsation due to dispensing syringe operation.

Using the created relative pressure waveform, create a pressure waveform reference (step S807). The pressure waveform reference to be created may be the obtained relative pressure waveform itself, or may be a feature quantity of the relative pressure waveform such as the average value of the pressure in a certain interval or the coordinates of the vertices of the waveform. If the same sample is dispensed multiple times with the same dispensed amount, it is recommended to create a representative pressure waveform reference using the average value or the median value. Further, both the sample serving as the reference for normal dispensing and the sample serving as the reference for dry aspiration may be used as the pressure waveform reference, or only the average thereof may be used as the pressure waveform reference.

The created pressure waveform reference is stored (step S808). By using the pressure waveform reference as the feature amount of the relative pressure waveform and storing only the feature amount, it is possible to reduce the amount of data to be stored.

After storing the pressure waveform reference (step S808), the calibration mode is terminated (step S809). Before ending the calibration mode (step S809), compare the time-series pressure data at the time of multiple dispensing to confirm that the difference is small, and if it is large, ask the service engineer or the user to perform calibration again Reliable pressure waveform reference can be improved by displaying alerts to encourage In addition to comparing time-series pressure data during multiple dispensing, comparing with the pressure waveform reference created in the previous calibration and confirming that the difference is small also has the effect of improving the reliability of the pressure waveform reference. There is Also, by creating the pressure waveform reference according to FIG. 8 at regular intervals, it is possible to make a highly reliable dry suction determination that cancels out long-term changes in the device.

It is desirable to create the pressure waveform reference on a day with average weather at the place where the device is installed. By creating a pressure waveform reference at the place where the device is installed, it is possible to determine dry suction without depending on changes in pressure pulsation due to external air pressure. Further, in order to cope with an environment in which the temperature changes greatly, it is preferable to correct the pressure waveform reference for the temperature and use it for air suction determination in order to improve the accuracy of the determination.

In this embodiment, by adopting a pressure reference value that is not affected by damped vibration due to inertial force, it is possible to detect the dispensing state with high accuracy without pressure pulsation due to probe operation before and after dispensing. In addition, by comparing the relative pressure waveform with respect to the pressure reference value with the pre-acquired pressure waveform reference, it is possible to detect the dispensing state without depending on the pressure pulsation caused by the dispensing syringe operation. The dispensing state detection here is applicable not only to empty aspiration but also to a wide range of cases of detecting an unintended dispensing state such as clogging in the channel. It is also possible to apply the result evaluation, such as indicating that the dispensing result is good when the pressure waveform at the time of dispensing and the pressure waveform reference are highly matched.
[Modification of Embodiment 1]
FIG. 9 is a modification of the schematic configuration diagram of the sample pipetting mechanism of the automatic analyzer of the above-described first embodiment shown in FIG. Below, the same reference numerals are given to the same constituent elements as in the first embodiment, and the description overlapping with the first embodiment is omitted.
As shown in FIG. 9, the difference from FIG. 2 is that the information of the liquid level sensor 222 is transmitted to the control unit 207 instead of the storage unit 220. FIG.

The liquid level sensor 222 determines whether the tip 201 at the tip of the probe 202 is immersed in the sample 209 during dispensing. In this modification, the immersion detection information of the liquid level sensor 222 is directly transmitted to the control unit 207, and after the immersion detection time, the probe 202 is lowered by a certain amount and then stopped. , the relative immersion depth of the probe 202 is kept constant.

In this modification, the immersion depth h in the above formula (2) is a constant value,
P _head =ρgH+α (3)
can be Here, α is a constant constant. In this case, it is not necessary to refer to the immersion depth h for each dispensing, and it is only necessary to refer to the probe height H.

FIG. 10 shows a method of determining the constant α in this modified example.
As shown in FIG. 10, in step S1001, pressure is acquired at probe height H0. It should be noted that the probe height H0 is acquired by the liquid level sensor 222 and the control unit 207 . Also, pressure is acquired by pressure sensor 214 , signal amplifier 216 , and determination unit 218 . Let the pressure acquired here be P0. Here, as H0, it is desirable that the height, such as the upper limit of the probe, is determined in advance. Moreover, it is desirable to acquire the pressure at a time when the pressure pulsation is small, such as when the probe is stationary or when the movement direction of the probe is perpendicular to the direction of the flow path. When the probe moves horizontally, the operating direction of the probe is perpendicular to the direction of the flow path, so pressure pulsation is small and this is suitable as a pressure acquisition time. Also, it is preferable to acquire the pressure in a certain time interval and use the average value as the pressure value.

Calculation of constant α (step S1002) can be performed by the following equation (4).
α=ρgH−P0 (4)
Using the constant α determined using the procedure of FIG. 10, the fluid pressure Phead based on the gravitational acceleration is calculated from the above equation (3), Phead is adopted as the reference pressure value, and dry suction determination is performed. .

Since the reference pressure value Phead calculated in the modification of this embodiment does not depend on the pressure pulsation caused by the probe operation before and after dispensing, it is possible to make a highly accurate determination without depending on the pressure pulsation.
Moreover, it is preferable to perform the procedure of FIG. 10 of the modified example of this embodiment for each dispensing cycle. By doing this for each dispensing cycle, if the pressure value measured by the pressure sensor 214 is offset during the entire dispensing cycle, or if bubbles enter the flow path, the fluid pressure based on the gravitational acceleration will change throughout the dispensing cycle. Even if there is a change, these influences can be canceled by calculating the reference pressure value Phead, so that it is possible to stably determine empty suction.

As described above, according to this embodiment, it is possible to provide an automatic analyzer capable of detecting the dispensing state with high accuracy even when pressure pulsation occurs due to the dispensing syringe operation or the probe operation before and after dispensing. becomes.
In addition, high-precision detection of the dispensing state enables high-precision detection of air bubbles generated by the user's handling of sample containers and fibrin that causes clogging. It is possible to provide an automatic analyzer that can save the user's trouble such as inspection.

FIG. 11 is a diagram showing a procedure for judging dry sucking in Example 2 according to another example of the present invention. Only the differences between this example and Example 1 are shown below.

As shown in FIG. 11, the present embodiment differs in that the processing from step S601 to step S604 in FIG. 6 of the first embodiment is replaced with the processing from step S1101 to step S1104 in FIG. Only steps S1101 to S1104 will be described below.

Pre-dispensing probe descent stop/stop time and channel position information acquisition (step S1101) are performed. Here, the channel position information may be obtained by acquiring only the probe height as in the first embodiment, or by using the channel position determination unit 223 as a sensor for determining the shape of the channel, and measuring the channel shape. may be performed. As for the stop time, pressure data including the probe lowering stop time 402 as shown in FIG. 4 may be obtained, and the probe lowering stop time 402 may be read from the pressure data.

Calculation of pressure pulsation (step S1103) due to stopping the downward movement before dispensing is performed on the data obtained in the dispensing syringe operation/time-series pressure data collection (step S1102).
FIG. 12 shows pressure data 1201 before pulsation processing obtained in dispensing syringe operation/time-series pressure data collection (step S1102), and pressure pulsation calculation due to pre-dispensing descent stop (step S1103). Pulsation processed pressure data 1203 with pressure pulsation 1202 subtracted is shown.
The descent stop pressure pulsation P _osc between the probe descent stop time 402 and the dispensing syringe operation start time 403 can be described, for example, by the damped oscillation equation (5) below.
P _osc =A×exp{−B(t−t0)}×sin{C(t−t0)+D}+E (5)
Here, t is the time, and t0 is the probe descent stop time. A, B, C, D, and E are constants that depend on the shape of the channel. It is possible to calculate _osc . Alternatively, the constants A, B, C, D, and E or the probe descent stop time t0 may be determined from the measurement data between the probe descent stop time 402 and the dispensing syringe operation start time 403. FIG. In addition, the vibration modeling is not limited to the expression (5), and various modifications such as adding high-order vibration components are conceivable, and these may be used.

By subtracting the descent stop pressure pulsation P _osc from the acquired pressure data 1201 before pulsation processing, pressure data 1203 after pulsation processing is obtained. By executing the relative pressure waveform generation procedure in FIG. It is possible to derive a relative pressure waveform that is not affected by pressure pulsation due to inertial force.

This embodiment is effective when the probe descent stop time 402 and the dispensing syringe operation start time 403 are close to each other, and the pressure pulsation due to the inertial force of the probe descent stop overlaps with the pressure pulsation due to the dispensing syringe operation. By deriving and subtracting the pressure pulsation P _osc due to the inertia force of stopping probe descent in this embodiment, it is possible to cancel the pressure pulsation due to the inertia force of stopping probe descent remaining after the dispensing syringe operation start time 403. . As a result, it is possible to pick out only the pressure pulsation due to the operation of the dispensing syringe and to perform highly accurate dispensing state detection.

As described above, according to the present embodiment, in addition to the effects of the first embodiment, the probe descent stop time 402 and the dispensing syringe operation start time 403 are close to each other, and the pressure pulsation caused by the inertial force of the probe descent stop causes the dispensing syringe operation. It is effective when it overlaps with the pressure pulsation caused by

In addition, the present invention is not limited to the above-described embodiments, and includes various modifications. For example, the above-described embodiments have been described in detail in order to explain the present invention in an easy-to-understand manner, and are not necessarily limited to those having all the described configurations. In addition, it is possible to replace part of the configuration of one embodiment with the configuration of another embodiment, and it is also possible to add the configuration of another embodiment to the configuration of one embodiment.

DESCRIPTION OF SYMBOLS 101...Automatic analyzer 102...Sample rack 103...Rack transport line 104...Reagent cooling unit 105...Incubator disk 106...Sample dispensing mechanism 107...Reagent dispensing mechanism 108...Consumables transport unit 109...Detection part unit 110...Sample container (Sample container)
Reference Signs List 111 Reagent container 112 Reagent disc cover 113 Reaction container 114 Reaction container placement unit 201 Chip 202 Probe 203 Flow path 204 Syringe 204 a Cylinder 204 b Plunger 205 Syringe driving unit 206 Probe driving unit 207 Control unit 208 Container 209 Specimen (sample)
210... Water supply pump 211... Water supply tank 212... Cleaning water 213... Solenoid valve 214... Pressure sensor 215... Branch block 216... Signal amplifier 217... A/D converter 218... Judgment part 219... Sampling part 220... Storage part 221... Calculation Section 222 Liquid level sensor 223 Flow path position determination section 224 Display section 301 Air bubble 401 Probe horizontal rotational movement stop time 402 Probe descent stop time 403 Dispensing syringe operation start time 404 Dispensing syringe operation end Time 701a Reference pressure value 701b Threshold pressure 702a Reference time 703a Origin 1201 Pressure data before pulsation 1202 Stop pressure pulsation 1203 Pressure data after pulsation

Claims (15)

having a vessel filled with fluid and a pressure source,
a probe for aliquoting the fluid in the container;
a driving unit for moving the probe;
a flow path connecting the probe and the pressure source;
a pressure sensor that measures pressure fluctuations in the channel;
a storage unit that stores time-series measurement data of the pressure sensor;
a sensor for detecting the liquid surface position in the container;
a position determination unit that determines the position of the channel or the probe;
with
The flow generated in the flow path based on the time-series measurement data and the fluid pressure based on the gravitational acceleration at the position of the pressure sensor calculated based on the position information of the flow path or the probe by the position determination unit. An automatic analyzer characterized by estimating a state. In the automatic analyzer according to claim 1,
determining a reference value of the pressure according to the fluid pressure based on the gravitational acceleration at the position of the pressure sensor calculated based on the positional information of the flow path or the probe by the position determination unit;
Subtracting the reference value from the time-series measurement data,
An automatic analyzer characterized by estimating the state of flow using time-series measurement data after subtraction. In the automatic analyzer according to claim 2,
determining a reference value of the pressure according to the fluid pressure based on the gravitational acceleration at the position of the pressure sensor calculated based on the positional information of the flow path or the probe by the position determination unit;
Determining a reference point of the time of the time-series measurement data using the reference value of the pressure,
An automatic analyzer, characterized in that the state of flow is estimated using time-series measurement data obtained by offsetting the reference point of time to zero. In the automatic analyzer according to claim 1,
An automatic analyzer, wherein a pressure pulsation is calculated according to a channel position and an operation history of the channel, and the calculated pressure pulsation is subtracted from the time-series measurement data. In the automatic analyzer according to any one of claims 1 to 4,
An automatic analyzer, wherein the time interval between the pressure generating operation of the pressure source and the operation of moving the channel is 1 second or less. In the automatic analyzer according to any one of claims 1 to 4,
An automatic analyzer, wherein the operation is adjusted so that the immersion depth of the probe with respect to the specimen immediately before the fluid sorting operation is constant by a sensor that detects the liquid surface position in the container. In the automatic analyzer according to claim 6,
An automatic analyzer characterized by storing time-series measurement data of pressure sensors at two or more channel positions. In the automatic analyzer according to claim 2 or claim 3,
An automatic analyzer characterized in that the viscosity of a sample for calibration in obtaining reference pressure data is 1.5 mPa·s or less in an environment of 25°C. having a vessel filled with fluid and a pressure source,
a probe for aliquoting the fluid in the container;
a driving unit for moving the probe;
a flow path connecting the probe and the pressure source;
a pressure sensor that measures pressure fluctuations in the channel;
a storage unit that stores time-series measurement data of the pressure sensor;
a sensor for detecting the liquid surface position in the container;
a position determination unit that determines the position of the channel or the probe;
with
estimating the state of the flow occurring in the flow channel based on the time-series measurement data and the position information of the flow channel or the probe by the position determination unit;
An automatic analyzer, wherein a pressure pulsation is calculated according to a channel position and an operation history of the channel, and the calculated pressure pulsation is subtracted from the time-series measurement data. In the automatic analyzer according to claim 9,
Determining a reference value of pressure according to the positional information of the flow channel or the probe by the position determination unit,
Subtracting the reference value from the time-series measurement data,
An automatic analyzer characterized by estimating the state of flow using time-series measurement data after subtraction. In the automatic analyzer according to claim 10,
Determining a reference value of pressure according to the positional information of the flow channel or the probe by the position determination unit,
Determining a reference point of the time of the time-series measurement data using the reference value of the pressure,
An automatic analyzer, characterized in that the state of flow is estimated using time-series measurement data obtained by offsetting the reference point of time to zero. In the automatic analyzer according to any one of claims 9 to 11,
An automatic analyzer, wherein the time interval between the pressure generating operation of the pressure source and the operation of moving the channel is 1 second or less. In the automatic analyzer according to any one of claims 9 to 11,
An automatic analyzer, wherein the operation is adjusted so that the immersion depth of the probe with respect to the specimen immediately before the fluid sorting operation is constant by a sensor that detects the liquid surface position in the container. In the automatic analyzer according to claim 13,
An automatic analyzer characterized by storing time-series measurement data of pressure sensors at two or more channel positions. In the automatic analyzer according to claim 10 or claim 11,
An automatic analyzer characterized in that the viscosity of a sample for calibration in obtaining reference pressure data is 1.5 mPa·s or less in an environment of 25°C.

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